ABSTRACT Effective therapeutic interventions are needed to stem the alarming increases in non-alcoholic fatty liver disease (NAFLD) in Mexican-American men, an understudied population at greater risk for the development of hepatocellular carcinoma (HCC). Primary lifestyle risk factors for NAFLD include physical inactivity and sugar- sweetened beverage consumption, characteristics that are highly evidenced in Mexican-American men. The risk of NAFLD is further increased in Mexican-American men by a greater frequency (up to 55%) of the risk allele at the PNPLA3 (patatin-like phospholipase domain-containing protein) gene. This allele confers a substantially greater susceptibility to NAFLD and HCC. In the absence of FDA-approved pharmaceutical agents, lifestyle modification, including weight loss initiated by improvements in dietary and physical activity behavior, is the recommended therapy for the prevention and treatment of NAFLD. Lifestyle interventions targeting modest weight loss (approximately 5% body weight) have been shown to result in significant reductions in liver fat. However, evidence regarding the effects of a lifestyle intervention designed exclusively for Mexican-American men at greater risk for NAFLD is not currently available. Dr. David Garcia has an excellent foundation in lifestyle interventions that has positioned him well to advance toward his goal of reducing obesity-related disease burden in Mexican-American males. The goal of this NIMHD K01 Mentored Research Scientist Development Award is to provide Dr. Garcia with an in-depth understanding of metabolic and pathogenic pathways and risk factors of obesity-related cancers and related diseases, with a specific focus on NAFLD and HCC in Mexican-American men. He also will gain training in non-invasive imaging biomarkers (e.g., transient elastography) for the evaluation and management of disease state and risk factors. Lastly, he will advance his knowledge and skill development in research methodologies (e.g., quantitative analysis and qualitative inquiry) that informs on the design and tailoring of a culturally-specific study to reduce the burden of NAFLD. With the mentorship of Dr. Cynthia Thomson and Dr. Michael Fallon, co-mentors, and collaborators; for the proposed project Dr. Garcia intends to 1) use an available dataset from the Cameron County Hispanic Cohort (CCHC) to assess risk for NAFLD, including the influence of phenotypic factors (lifestyle behaviors) in Mexican-American men; 2) evaluate the knowledge, attitudes, and beliefs of obesity-related cancer risk, with an emphasis on NAFLD and HCC risk in Mexican-American men; and 3) assess the feasibility, acceptability, and preliminary efficacy of a NAFLD-specific weight loss intervention tailored for Mexican-American men. The training plan and research strategy in this K01 application will afford Dr. Garcia the time, resources, and mentorship necessary to achieve his career goal which is enthusiastically endorsed by University of Arizona leaders and an extremely appropriate and supportive research environment.